The Correlation Between Serum Estrogen Level And The Expression Of Mismatch Repair Genes In Colonic Epithelial Cells Of Healthy Individuals

Background and AimsThe DNA mismatch repair (MMR) system plays a key role in maintaining genomic stability. Patients with germline mutations of any of the 4 major MMR genes (hMSH2, hMLH1, hMSH6, or hPMS2) have Lynch syndrome (or hereditary nonpolyposis colorectal cancer [HNPCC]), the most common familial form of colorectal cancer. Another 10-15% of sporadic colorectal cancers are caused by epigenetic silencing of hMLH1 gene. MMR dysfunction causes microsatellite instability (MSI). It has been reported that in HNPCC families, the incidence of colorectal cancer (CRC) is higher in male mutation carriers than in female, which was found similar in Chinese HNPCC families. The sex-specific difference in incidence of HNPCC has been attributed to estrogen. It has been reported that post-menopausal estrogen replacement therapy can reduce the risk of MSI-positive colon cancer. These findings suggest that estrogen might prevent CRC caused by MMR dysfunction. In fact, estrogen has been reported to have a protective effect on colon cancer in several large-scale population studies; however the underlying mechanism is unclear. These above studies provide foundation for the hypothesis that estrogen may prevent carcinogenesis by altering the expression and function of DNA MMR gene(s) in colonic cells. However, there has been no examination of the effects of estrogen on MMR gene expression in colonic epithelial cells. Therefore, this study investigated the correlation between serum estrogen level and the expression of two representative MMR genes (hMLH1 and hMSH2) in human colonic epithelial cells from healthy individuals.Materials and MethodsA total of 42 healthy individuals underwent colonoscopy were enrolled in the study. Blood was taken half an hour before colonoscopy for determining the serum estradiol (E2) level. Under colonoscopic examination, normal colonic mucosal tissues were taken in the right hemicolon. The tissues were used to extract total RNA for semi-quantitative RT-PCR or fixed with formalin, and then embedded in paraffin for immunohistochemical staining. The relative levels of mRNA and positivity index (PI) of immunohistochemical staining were calculated to evaluate the expression of hMLH1 and hMSH2. Then the association of serum E2 levels and the target genes expression was analyzed.ResultsA bimodal curve for the correlation of hMLH1 expression and serum E2 level in vivo was presented. Curved estimation showed that cubic equation model was the best model to analyze the correlation. Furthermore, the stratified analysis showed this model was more significant in the female subjects. A strong positive correlation of E2 level with hMLH1 expression in normal colonic epithelial cell was observed when serum E2 level was more than 45pg/ml. But no correlation was seen between E2 and hMSH2 expression.ConclusionEstradiol may increase the expression of hMLH1 in normal colonic epithelial cell. Estrogen might prevent colon cancer by regulating MMR system, and the interplay between cell proliferation control and MMR dysfunction at low E2 level may lead to occurrence of colonic cancer.